Phone: (518) 641-6466
Fax: (518) 641-6304
hkimelberg@ordwayresearch.org

Research Focus

Dr. Kimelberg’s research interests center on the role of astroglia or astrocytes. These cells are numerous cells in the brain which coexist with the better studied neurons, and are so named because most have a star-shaped appearance under the microscope. One important aspect of the research in the Nerve Cell Rescue Laboratory is whether malfunctions of these cells contribute to the early damage in stroke and traumatic brain injury and thus are potential targets for therapy. Dr. Kimelberg’s group has been exploring the use of blockers of the excessive release of an excitatory chemical messenger in the brain, glutamic acid, which is normally released from neurons in a controlled manner for communication between these cells and then is taken up by the astrocytes to stop further activity.

Astrocytes are as numerous as neurons and closely surround blood vessels in the brain, and Dr. Kimelberg is well recognized as a pioneer researcher in probing their functions. Many of their properties are similar to those seen in neurons , such as they have receptors for various brain chemical transmitters, so it is a challenge to sort out which of the brain’s functions are due to neurons and which to astrocytes. The laboratory studies the basic properties of these cells as cultured and freshly isolated cells or in situ in slices by a combination of patch clamp electrophysiology, immunocytochemistry and mRNA analysis. New ideas on astrocyte cellular heterogeneity and function are emerging from this work.

Astrocytes rapidly swell in a number of pathological states affecting the mammalian CNS. The recent discovery that most of the water channels or aquaporins (for whose discovery the Nobel Prize for chemistry was awarded in 2003) in the brain are to be found in astrocytes adds further interest to and tools for studying astrocytic swelling. This swelling is the main underlying condition of cytotoxic or cellular edema. Dr. Kimelberg and his team are interested in elucidating the mechanisms and consequences of such edema. On one hand they study these processes in astrocyte cultures studying the second messenger signaling cascades leading to release of EAAs in response to hypotonic solutions or raised medium K⁺. They have also found that released transmitters such as ATP or nitric oxide products potentiate astrocyte-swelling induced EAA release. The team also studies the anion channels thought to be the principal route of such release, by patch-clamp electrophysiology techniques in freshly isolated astrocytes or astrocytes in situ, and seek to identify this channels or channels, a critical step that has so far eluded the field.

Astrocytic swelling, as noted above, is an early event in cerebral trauma and ischemia, and is referred to as cytotoxic or cellular brain edema and is observed within the earliest measured times of 1 to 2 hours after stroke onset in humans by diffusion-weighted MR imaging. Dr. Kimelberg and The Nerve Cell Rescue Laboratory team found, starting 25 years ago, that anion transport inhibitors inhibit such swelling occurring 40 minutes after trauma-hypoxia head injury in cats and also significantly improved neurological recovery and decreased mortality when injected either intravenously or directly into the CNS via the cisterna magna. The same inhibitors also reduced infarct size in a rabbit ischemia model. These compounds also inhibit release of excitatory amino-acids from swollen astrocyte cultures, suggesting a possible mechanism for the protective action of these compounds. The laboratory now uses microdialysis to study release of excitatory amino-acids in vivo in a rat focal ischemia model and has shown that the increase can be mainly accounted for by release via the swelling activated channels and reversal of the astrocytic GLT-1 transporter. They have recently identified an inhibitor of EAA release, tamoxifen, as a very effective neuro-protectant in rat ischemic models. They seek to study the mechanisms of its neuroprotection in more detail in animal models and then set up a clinical trial to test its use as a neuroprotectant in stroke, as there are presently no neuroprotectants approved for such use.

Dr. Kimelberg has authored or been a co-author of around 250 reviews and experimental papers, has served on the editorial boards of numerous journals, reviews grants for NIH and other national and international agencies, and has presented the work of his laboratory in invited seminars and as a speaker at meetings both here and abroad. He has been the recipient of a Fulbright senior Professorship to study at the University of Heidelberg in 1988. He has graduated six Ph.D. and two master's students.

Selected References

www.pubmed.com

Abdullaev IF, Rudkouskaya A, Schools GP, Kimelberg HK, Mongin AA (2006) Pharmacological comparison of swelling-activated excitatory amino acid release and Cl- currents in rat cultured astrocytes. J Physiol 572.3: 677-689.

Haskew-Layton RE, Mongin AA, Kimelberg HK (2005) Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via a mechanism involving Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 280: 3548-3554.

Kimelberg HK (2004) Water transport in the brain: basic concepts. Neurosci 129: 851-860.

Kimelberg HK (2005) Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50: 389-397.

Mongin AA, Kimelberg HK (2005) ATP regulates anion channel-mediated organic osmolyte release from cultured rat astrocytes via multiple Ca2+-sensitive mechanisms. Am J Physiol Cell Physiol 288: C204-C213.

Zhang Y, Jin Y, Behr MJ, Feustel PJ, Morrison JP, Kimelberg HK (2005) Behavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia. Exp Neurol 196: 41-46.

Zhou M, Schools GP, Kimelberg HK (2006) Development of GLAST(+) astrocytes and NG2(+) glia in rat hippocampus CA1: mature astrocytes are electrophysiologically passive. J Neurophysiol 95: 134-143.

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